The U54 Cooperative Contraceptive Development Research Center Grant described in this proposal includes five projects. We identified new leads to be developed into safe and effective contraceptives both for men and women and with additional health benefits to the users: (I) A new contraceptive vaginal ring will be developed using Nestorone (NES) and natural Estradiol (E2) for a safer contraception. SA1: NES/E2 rings will be designed for a first efficacy study. Potential benefits on the brain will be tested by: SA2 determining impact of hormone exposure on neurogenesis in normal brain and SA3 will evaluate the effects of NES and E2, on myelin repair both on in vitro and in vivo animal models. (II) A new progesterone receptor modulator Ulipristal (UPA/CDB-2914) will be investigated: SA1: Endometrial safety and contraceptive efficacy of a 3-month UFA vaginal ring (UPA CVR) in combination with progestin will be assessed in a 6- month clinical study. SA2: A contraceptive intrauterine system (IDS) releasing low doses of UPA to decrease endometrium and bleeding will be developed SA3: Molecular mechanisms underlying potential benefits of UPA CVR will be tested on target tissues. (Ill) The evaluation of new endothelin receptor antagonists on ovulation with the goal of developing new specific and highly effective emergency contraceptives will be conducted in collaboration with the University of Illinois (IV) MENT(r) Ac implants for male contraception with added health benefits will be tested. We will (SA1) Manufacture new one-year MENT Ac subdermal implants to (SA2) conduct an efficacy & safety study on the effect of implants alone and with Depomedroxyprogesterone acetate (DMPA) in normal men. We will: SA3: evaluate the mechanism of action of MENT when combined with progestins; SA4: evaluate the protective effect of MENT on Leydig Cells; SA5: confirm protective effects of MENT on bone when combined with DMPA. (V): Develop adjudin as a nonhormonal male contraceptive; SA1: characterize the formulation (adjudin-IMB) for clinical use in men. SA2: Unravel molecular mechanism(s) by which adjudin-IMB disrupts adhesion protein complexes at the apical ectoplasmic specialization. SA3: Complete toxicity program to prepare for clinical use in men.